Asymmetric Mannich Reaction of Isatin-Derived Ketimines with α-Fluoroindanones Catalyzed by a Chiral Phase-Transfer Catalyst.

A highly enantioselective Mannich reaction of α-fluoroindanones with isatin-derived N-Boc-ketimines catalyzed by a quinine-derived phase-transfer catalyst was developed. A variety of 3-substituted 3-amino-2-oxindoles bearing fluorine-containing, vicinal, tetrasubstituted stereocenters were constructed using this protocol in high yields (83-95%), with moderate to excellent enantioselectivities (66-91%) and high diastereoselectivities (up to >99:1).

The value of deep learning-based computer aided diagnostic system in improving diagnostic performance of rib fractures in acute blunt trauma.

BACKGROUND: To evaluate the value of a deep learning-based computer-aided diagnostic system (DL-CAD) in improving the diagnostic performance of acute rib fractures in patients with chest trauma. MATERIALS AND METHODS: CT images of 214 patients with acute blunt chest trauma were retrospectively analyzed by two interns and two attending radiologists independently firstly and then with the assistance of a DL-CAD one month later, in a blinded and randomized manner. The consensusdiagnosis of fib fracture by another two senior thoracic radiologists was regarded as reference standard. The rib fracture diagnostic sensitivity, specificity, positive predictive value, diagnostic confidence and mean reading time with and without DL-CAD were calculated and compared. RESULTS: There were 680 rib fracture lesions confirmed as reference standard among all patients. The diagnostic sensitivity and positive predictive value of interns weresignificantly improved from (68.82%, 84.50%) to (91.76%, 93.17%) with the assistance of DL-CAD, respectively. Diagnostic sensitivity and positive predictive value of attendings aided by DL-CAD (94.56%, 95.67%) or not aided (86.47%, 93.83%), respectively. In addition, when radiologists were assisted by DL-CAD, the mean reading time was significantly reduced, and diagnostic confidence was significantly enhanced. CONCLUSIONS: DL-CAD improves the diagnostic performance of acute rib fracture in chest trauma patients, which increases the diagnostic confidence, sensitivity, and positive predictive value for radiologists. DL-CAD can advance the diagnostic consistency of radiologists with different experiences.

YAP1 protects against PM2.5-induced lung toxicity by suppressing pyroptosis and ferroptosis.

Pollution from fine particulate matter (PM2.5) has become a major threat to public health and has been related to lung toxicity. One of the key regulators of the Hippo signaling system, Yes-associated protein 1 (YAP1), is speculated to play a role in ferroptosis development. Here, we focused on investigating the function of YAP1 in pyroptosis and ferroptosis, aiming to explore its therapeutic potential in PM2.5-induced lung toxicity. PM2.5-induced lung toxicity was induced in Wild-type WT and conditional YAP1-knockout mice, and lung epithelial cells were stimulatd by PM2.5 in vitro. We used western blot, transmission electron microscopy, and fluorescence microscopy to investigate pyroptosis- and ferroptosis-related characteristics. We found that PM2.5 leads to lung toxicity using mechanisms involving pyroptosis and ferroptosis. YAP1 knockdown impeded pyroptosis, ferroptosis, and PM2.5-induced lung damage, as shown by increased histopathology, higher levels of proinflammatory cytokines, GSDMD protein, lipid peroxidation, and iron accumulation, as well as increased NLRP3 inflammasome activation and decreased SLC7A11 expression. YAP1 silencing consistently promoted NLRP3 inflammasome activation and reduced SLC7A11 levels, aggravating PM2.5-induced cellular damage. In contrast, YAP1-overexpressing cells inhibited NLRP3 inflammasome activation and increased SLC7A11 levels, preventing pyroptosis and ferroptosis. Overall, our data suggest that YAP1 ameliorates PM2.5-induced lung injury by inhibiting NLRP3-mediated pyroptosis and SL7A11-dependent ferroptosis.

Development and validation of a 3D-convolutional neural network model based on chest CT for differentiating active pulmonary tuberculosis from community-acquired pneumonia.

PURPOSE: To develop and validate a 3D-convolutional neural network (3D-CNN) model based on chest CT for differentiating active pulmonary tuberculosis (APTB) from community-acquired pneumonia (CAP). MATERIALS AND METHODS: Chest CT images of APTB and CAP patients diagnosed in two imaging centers (n = 432 in center A and n = 61 in center B) were collected retrospectively. The data in center A were divided into training, validation and internal test sets, and the data in center B were used as an external test set. A 3D-CNN was built using Keras deep learning framework. After the training, the 3D-CNN selected the model with the highest accuracy in the validation set as the optimal model, which was applied to the two test sets in centers A and B. In addition, the two test sets were independently diagnosed by two radiologists. The 3D-CNN optimal model was compared with the discrimination, calibration and net benefit of the two radiologists in differentiating APTB from CAP using chest CT images. RESULTS: The accuracy of the 3D-CNN optimal model was 0.989 and 0.934 with the internal and external test set, respectively. The area-under-the-curve values with the 3D-CNN model in the two test sets were statistically higher than that of the two radiologists (all P < 0.05), and there was a high calibration degree. The decision curve analysis showed that the 3D-CNN optimal model had significantly higher net benefit for patients than the two radiologists. CONCLUSIONS: 3D-CNN has high classification performance in differentiating APTB from CAP using chest CT images. The application of 3D-CNN provides a new automatic and rapid diagnosis method for identifying patients with APTB from CAP using chest CT images.

CT quantitative analysis of pulmonary changes in rheumatoid arthritis.

OBJECTIVE: To explore the application of quantitative computed tomography (CT) in analyses of lung changes in patients with rheumatoid arthritis (RA). METHODS: A total of 150 clinically diagnosed RA patients underwent chest CT and 150 matched non-smokers subjects with normal chest CT are enrolled. A CT software is applied to analyze CT obtained from both groups. The quantitative indices of emphysema are expressed as the percentage of lung area with attenuation < -950HU to the total lung volume (LAA-950%), and pulmonary fibrosis was expressed as the percentage of lung area with a attenuation of -200 to -700HU to the total lung volume (LAA-200--700%), quantitative indicators of pulmonary vascular include aortic diameter (AD), pulmonary artery diameter (PAD), the ratio of PAD to AD (PAD/AD ratio), the number of blood vessels (TNV), and the cross area of blood vessels (TAV). The receiver operating characteristic (ROC) curve is used to evaluate the ability of these indexes in identifying the changes in the lung in RA patients. RESULTS: Compared to the control group, the RA group has significantly lower TLV, larger AD, and smaller TNV and TAV (3921±1101 vs. 4490±1046, 33.26±4.20 vs. 32.95±3.76, 13.14±4.93 vs. 17.53±3.34, and 96.89±40.62 vs. 163.32±34.97, respectively, with all p < 0.001). Peripheral vascular indicator TAV has the better ability to identify lung changes in RA patients (area under ROC curve AUC = 0.894) than TNV (AUC = 0.780) or LAA-200 &sim-700% (AUC = 0.705). CONCLUSION: Quantitative CT can detect changes in lung density distribution and peripheral vascular injury in patients with RA and assess the severity.

Aymmetric Aza-Friedel-Crafts Reaction of Isatin-Derived Ketimines with Indoles Catalyzed by a Chiral Phase-Transfer Catalyst.

A highly enantioselective aza-Friedel-Crafts reaction of 1H-indoles with isatin-derived N-Cbz-ketimines catalyzed by quinine-derived phase-transfer catalysts was developed. A series of chiral 3-aminobisindole compounds containing a tetrasubstituted stereocenter were constructed by this protocol in high yields (82-91%) and moderate to excellent enantioselectivities (46-94% ee).

Activating transcription factor 5 (ATF5) promotes tumorigenic capability and activates the Wnt/b-catenin pathway in bladder cancer.

BACKGROUND: In bladder cancer, up to 70% of patients will relapse after resection within 5 years, in which the mechanism underlying the recurrence remains largely unclear. METHODS: Quantitative real-time PCR, western blot and immunohistochemistry were conducted. The assays of tumor sphere formation and tumor xenograft were further performed to assess the potential biological roles of ATF5 (activating transcription factor 5). Chromatin immunoprecipitation-qPCR and luciferase activity assays were carried out to explore the potential molecular mechanism. A two-tailed paired Student's t-test, χ2 test, Kaplan Meier and Cox regression analyses, and Spearman's rank correlation coefficients were used for statistical analyses. RESULTS: ATF5 is elevated in bladder urothelial cancer (BLCA) tissues, especially in recurrent BLCA, which confers a poor prognosis. Overexpressing ATF5 significantly enhanced, whereas silencing ATF5 inhibited, the capability of tumor sphere formation in bladder cancer cells. Mechanically, ATF5 could directly bind to and stimulate the promoter of DVL1 gene, resulting in activation of Wnt/ß-catenin pathway. CONCLUSIONS: This study provides a novel insight into a portion of the mechanism underlying high recurrence potential of BLCA, presenting ATF5 as a prognostic factor or potential therapeutic target for preventing recurrence in BLCA.

Effect of New Model-Based Iterative Reconstruction on Quantitative Analysis of Airway Tree by Computer-Aided Detection Software in Chest Computed Tomography.

OBJECTIVE: Compared the performance of computer-aided detection (CAD) software for quantitative analysis of airway using computed tomography (CT) images reconstructed with versions of model-based iterative reconstruction (MBIR) that either balances spatial and density resolution (MBIRSTND) or prefers spatial resolution (MBIRRP20), and adaptive statistical iterative reconstruction (ASIR) with lung kernel. METHODS: Thirty patients were included who were scanned for pulmonary disease using a routine dose multidetector CT system. Data were reconstructed with ASIR, MBIRSTND, and MBIRRP20. Airway dimensions from the 3 reconstructions were measured using an automated, quantitative CAD software designed to segment and quantify the bronchial tree automatically using a skeletonization algorithm. For each patient and reconstruction algorithm, the right middle lobe bronchus was selected as a representative for measuring the bronchial length of the matched airways. Two radiologists used a semiquantitative 5-point scale to rate the subjective image quality of MBIRSTND and MBIRRP20 reconstructions on airway trees analysis. RESULTS: Algorithm impacts the measurement variability of bronchus length in chest CT, MBIRRP20 were the best, whereas ASIR were the worst (P < 0.05). In addition, the optimal reconstruction algorithm was found to be MBIRSTND for the airway trees being assessed about subjective noise and MBIRRP20 about bronchial end shows, and there were no significant differences in the continuity and completeness of bronchial wall, whereas ASIR performed inferiorly compared with them (P < 0.05). CONCLUSIONS: Compared with ASIR, MBIRSTND, and MBIRRP20 from MBIRn algorithm potentially allow the desired airway quantification accuracy to be achieved on the performance of CAD, especially for MBIRRP20.

Energy output modalities of shockwave lithotripsy in the treatment of urinary stones: escalating or fixed voltage? A systematic review and meta-analysis.

PURPOSE: To compare the effectiveness and safety of escalating and fixed energy output modalities of shockwave lithotripsy (SWL) in the treatment of urinary stones. METHODS: A systematic literature search using PubMed, Embase, Cochrane Library and Web of Science was performed to obtain relevant studies up to December 2018. Summarized mean differences (MDs) and risk differences (RDs) with 95% confidence intervals (CIs) were used for comparing continuous and dichotomous variables, respectively. RESULTS: Six RCTs including 775 patients were identified. In the overall pooled outcomes, no significant difference was detected between escalating and fixed voltage group regarding initial and final success rate (SR) and stone-free status (SFS), auxiliary procedure and complication (hematoma, febrile episode, and pain) rate. However, when shockwave frequency ≥ 90 shocks/min, total shocks per session ≤ 3000, or 1-3 SWL sessions were performed, escalating group was associated with significantly higher SR1 (defined as SFS + fragments ≤ 4 mm); in addition, escalating group brought significantly less hematoma when total shocks per session ≤ 3000. CONCLUSIONS: Escalating voltage SWL offered comparable safety and effectiveness to that of fixed voltage SWL. However, escalating voltage SWL could be recommended in following conditions: (1) shockwave frequency ≥ 90 shocks/min, total shocks per session ≤ 3000, or 1-3 SWL sessions, for better stone removal; (2) total shocks per session ≤ 3000, for less hematoma formation.

Synthesis of 4-Azaindolines Using Phase-Transfer Catalysis via an Intramolecular Mannich Reaction.

A series of bifunctional asymmetric phase-transfer catalysts containing novel fluorine-containing urea groups derived from cinchona alkaloids have been synthesized and successfully applied in the asymmetric intramolecular Mannich reaction. The 4-azaindoline products bearing multiple substrates were obtained in excellent yield (90-99%), with high enantioselectivity (up to 95%) and diastereoselectivity (up to >99:1).

Enantioselective addition of thiols to trifluoromethyl ketimines: synthesis of N,S-ketals.

An efficient enantioselective addition of thiols to acyclic trifluoromethyl ketimines has been established by using a bifunctional squaramide catalyst, which was derived from quinine, and the reaction was completed in 5 to 10 min. The construction of chiral tetrasubstituted carbon centers bearing trifluoromethylated N,S-ketals has been achieved in high yields (up to 96% yield) with excellent enantioselectivities (up to 99% ee).

Is fractal dimension a reliable imaging biomarker for the quantitative classification of an intervertebral disk?

PURPOSE: This study aimed to explore the feasibility of the fractal method used in decoding disk heterogeneity, hoping to find a reliable imaging biomarker for the quantitative and continuous grading of intervertebral disks (IVDs). METHODS: Totally, 180 IVDs in 65 low back pain patients (29 males, 36 female, 28-69 years) were examined with MRI. Each IVD was manually segmented on axial slice (at the mid-height layer of the disk). All disks were visually evaluated regarding degeneration grade, using Pfirrmann classification, by two experienced radiologists. Fractal dimension (FD) of the IVD was calculated from the defined regions of interest and correlated with Pfirrmann grade. RESULTS: Fractal dimension differed significantly between any two groups (P < 0.01). The mean FDs for the four grades were as follows: Pfirrmann 1: 1.13 ± 0.02; Pfirrmann 2: 1.30 ± 0.05; Pfirrmann 3: 1.50 ± 0.05; and Pfirrmann 4: 1.65 ± 0.02. The well-hydrated IVDs displayed low fractal dimension. Degenerated IVDs displayed increased fractal dimension caused by disk heterogeneity, where the fractal dimension was shown to correlate strongly with Pfirrmann grade. CONCLUSIONS: Fractal dimension associated well with IVD degeneration, determined with Pfirrmann grading, suggesting that the IVD fractal analysis was a suitable detection tool for the objective and continuous classification of IVD degeneration. These slides can be retrieved under Electronic Supplementary Material.

Outcomes of long-term follow-up of asymptomatic renal stones and prediction of stone-related events.

OBJECTIVES: To evaluate the long-term outcomes of patients undergoing observation of asymptomatic renal calculi and identify factors associated with stone-related events. PATIENTS AND METHODS: Patients with asymptomatic renal calculi electing active surveillance of their stones were retrospectively reviewed. Patients underwent annual ultrasonography and clinical visits with standardised questions regarding the development of symptoms or complications from calculi. Spontaneous stone passage, stone growth, development of stone-related symptoms, and requirement for intervention during follow-up were deemed as stone-related events. RESULTS: Between 2007 and 2017, 293 patients were reviewed to evaluate the natural history of asymptomatic renal calculi. The mean follow-up was 4.2 years. Overall incidences of spontaneous passage, stone growth, development of stone-related symptoms, and requirement of intervention were 32.1%, 16.7%, 28.3% and 12.3%, respectively. Stones >5 mm and lower pole stones were significantly less likely to pass spontaneously. Patients with diabetes mellitus (DM), hyperuricaemia or non-lower calyceal stone were more likely to experience stone growth. Stones >5 mm or non-lower pole stones were more likely to become symptomatic. Significant predictors of surgical intervention were stone size (>5 mm) and patients' age (>60 years). Primary therapy was extracorporeal shockwave lithotripsy in 33 patients and flexible ureteroscopy in three. CONCLUSION: The natural history of asymptomatic renal stones rarely requires intervention, although they do have a slightly higher rate of symptomatic events and growth over the intermediate term. In particular, patients with stones >5 mm, DM, hyperuricaemia, or non-lower calyceal stones are at higher risk of developing stone-related events, and should therefore be recommended for regular follow-up.

Balloon dilation for failed pyeloplasty in children?

OBJECTIVE: Pyeloplasty is considered the gold standard treatment for ureteropelvic junction obstruction (UPJO). However, the failure rate of pyeloplasty is as high as 10% and repeat pyeloplasty is more difficult. This study aimed to evaluate the efficacy of balloon dilatation for failed pyeloplasty in children. MATERIALS AND METHODS: Between 2011 and 2017, 15 patients, aged 6 months to 14 years, were treated with balloon dilation for restenosis of UPJO after a failed pyeloplasty. Ultrasound and intravenous urography were used to evaluate the primary outcome. Success was defined as the relief of symptoms and improvement of hydronephrosis, which was identified by ultrasound at the last follow-up. RESULTS: All patients successfully completed the operation, 13 patients by retrograde approach and 2 patients by antegrade approach. Thirteen patients were followed for a median of 15 (4 to 57) months and 2 patients were lost to follow-up. Resolution of the hydronephrosis was observed in 5 cases. The anteroposterior diameter (APD) of the pelvis decreased by an average of 12.4 ± 14.4mm. Eight patients needed another surgery. The average postoperative hospital stay was 1.78 ± 1.4 days. Two patients experienced fever after balloon dilation. No other complications were found. CONCLUSIONS: Balloon dilatation surgery is safe for children, but it is not recommended for failed pyeloplasty in that group of patients, owing to the low success rate.

GMars-T Enabling Multimodal Subdiffraction Structural and Functional Fluorescence Imaging in Live Cells.

Fluorescent probes with multimodal and multilevel imaging capabilities are highly valuable as imaging with such probes not only can obtain new layers of information but also enable cross-validation of results under different experimental conditions. In recent years, the development of genetically encoded reversibly photoswitchable fluorescent proteins (RSFPs) has greatly promoted the application of various kinds of live-cell nanoscopy approaches, including reversible saturable optical fluorescence transitions (RESOLFT) and stochastic optical fluctuation imaging (SOFI). However, these two classes of live-cell nanoscopy approaches require different optical characteristics of specific RSFPs. In this work, we developed GMars-T, a monomeric bright green RSFP which can satisfy both RESOLFT and photochromic SOFI (pcSOFI) imaging in live cells. We further generated biosensor based on bimolecular fluorescence complementation (BiFC) of GMars-T which offers high specificity and sensitivity in detecting and visualizing various protein-protein interactions (PPIs) in different subcellular compartments under physiological conditions (e.g., 37 °C) in live mammalian cells. Thus, the newly developed GMars-T can serve as both structural imaging probe with multimodal super-resolution imaging capability and functional imaging probe for reporting PPIs with high specificity and sensitivity based on its derived biosensor.

Novel Therapeutic Strategies for Solid Tumor Based on Body's Intrinsic Antitumor Immune System.

The accumulation of mutated somatic cells due to the incompetency of body's immune system may lead to tumor onset. Therefore, enhancing the ability of the system to eliminate such cells should be the core of tumor therapy. The intrinsic antitumor immunity is triggered by tumor-specific antigens (TSA) or TSA-sensitized dendritic cells (DC). Once initiated, specific anti-tumor antibodies are produced and tumor-specific killer immune cells, including cytotoxic T lymphocytes (CTL), NK cells, and macrophages, are raised or induced. Several strategies may enhance antitumor action of immune system, such as supplying tumor-targeted antibody, activating T cells, enhancing the activity and tumor recognition of NK cells, promoting tumor-targeted phagocytosis of macrophages, and eliminating the immunosuppressive myeloid-derived suppressor cells (MDSCs) and Treg cells. Apart from the immune system, the removal of tumor burden still needs to be assisted by drugs, surgery or radiation. And the body's internal environment and tumor microenvironment should be improved to recover immune cell function and prevent tumor growth. Multiple microenvironment modulatory therapies may be applied, including addressing hypoxia and oxidative stress, correcting metabolic disorders, and controlling chronic inflammation. Finally, to cure tumor and prevent tumor recurrence, repairing or supporting therapy that consist of tissue repair and nutritional supplement should be applied properly.

TEM8 functions as a receptor for uPA and mediates uPA-stimulated EGFR phosphorylation.

BACKGROUND: TEM8 is a cell membrane protein predominantly expressed in tumor endothelium, which serves as a receptor for the protective antigen (PA) of anthrax toxin. However, the physiological ligands for TEM8 remain unknown. RESULTS: Here we identified uPA as an interacting partner of TEM8. Binding of uPA stimulated the phosphorylation of TEM8 and augmented phosphorylation of EGFR and ERK1/2. Finally, TEM8-Fc, a recombinant fusion protein comprising the extracellular domain of human TEM8 linked to the Fc portion of human IgG1, efficiently abrogated the interaction between uPA and TEM8, blocked uPA-induced migration of HepG2 cells in vitro and inhibited the growth and metastasis of human MCF-7 xenografts in vivo. uPA, TEM8 and EGFR overexpression and ERK1/2 phosphorylation were found co-located on frozen cancer tissue sections. CONCLUSIONS: Taken together, our data provide evidence that TEM8 is a novel receptor for uPA, which may play a significant role in the regulation of tumor growth and metastasis.

Bifunctional Thiourea-Ammonium Salt Catalysts Derived from Cinchona Alkaloids: Cooperative Phase-Transfer Catalysts in the Enantioselective Aza-Henry Reaction of Ketimines.

An efficient enantioselective aza-Henry reaction of aryl α-ketoester-derived ketimines has been realized by using bifunctional thiourea-ammonium salt phase-transfer catalysts, which were derived from quinine. A variety of aryl α-ketoester-derived N-Ts ketimines were investigated, and the corresponding products were obtained in high to excellent yields (up to 99%) with good to high enantioselectivities (up to >99% ee).

Direct enantio- and diastereoselective Mannich reactions of isatin-derived ketimines with oxo-indanecarboxylates catalyzed by chiral thiourea derived from hydroquinidine.

A highly diastereo- and enantioselective Mannich reaction of isatin-derived ketimines with oxo-indanecarboxylates catalyzed by chiral thiourea derived from hydroquinidine has been developed. A series of 3-substituted 3-amino-oxindoles containing assembled bicyclic rings linked by a C-C bond were constructed by this protocol in excellent yields (92-99%) with high enantioselectivities (85-99% ee) and diastereoselectivities (up to >99 : 1 dr).

Enantio- and Diastereoselective Nitro-Mannich Reaction of α-Aryl Nitromethanes with Amidosulfones Catalyzed by Phase-Transfer Catalysts.

A high-yield, highly diastereo- and enantioselective nitro-Mannich reaction of α-aryl nitromethanes with amidosulfones catalyzed by a novel chiral phase-transfer catalyst, bearing multiple H-bonding donors, derived from quinine was developed. A variety of α-aryl nitromethanes and amidosulfones were investigated; and the corresponding products were obtained in excellent yields with excellent diastereo- and enantioselectivities (up to 99% yield, > 99:1 dr and >99% ee). As a demonstration of synthetic utility, the resulting ß-nitroamines could be converted to corresponding meso-symmetric and optically pure unsymmetric anti-1,2-diarylethylenediamines.